tbuckley/cabot-search huggingface dataset:
Safely Increasing Heart Transplantation with Donation after Cardiac Death
Authors: Nancy K. Sweitzer
Journal: New England Journal of Medicine (2023)

Heart failure affects more than 6 million persons in the United States. Advanced heart failure, which may result in refractory symptoms, frequent hospitalizations, and death, occurs in an estimated 15% of persons who receive a diagnosis of systolic dysfunction.1 Of these hundreds of thousands of persons, a few thousand receive a heart transplant each year — but 9% of patients on the transplantation list die waiting.2 Safely increasing the number of heart donors is critical to meeting demand. The current pool of suitable hearts is small and relies on donor hearts obtained after declaration of brain death. In the absence . . .
Human Papilloma Virus DNA Detection in Clinical Samples Using Fluorogenic Probes Based on Oligonucleotide Gated Nanoporous Anodic Alumina Films
Authors: Andy Hernández‐Montoto, M. Nieves Aranda, Isabel Caballos, Alba López‐Palacios, María Ángeles Tormo‐Mas, Javier Pemán, Mireya Prieto Rodríguez, Carlos Picornell, Elena Aznar, Ramón Martínez‐Máñez
Journal: Advanced Healthcare Materials (2023)

In this work, fluorogenic probes based on oligonucleotide capped nanoporous anodic alumina films are developed for specific and sensitive detection of human papilloma virus (HPV) DNA. The probe consists of anodic alumina nanoporous films loaded with the fluorophore rhodamine B (RhB) and capped with oligonucleotides bearing specific base sequences complementary to genetic material of different high-risk (hr) HPV types. Synthesis protocol is optimized for scale up production of sensors with high reproducibility. The sensors' surfaces are characterized by scanning electron microscopy (HR-FESEM) and atomic force microscopy (AFM) and their atomic composition is determined by energy dispersive X-ray spectroscopy (EDXS). Oligonucleotide molecules onto nanoporous films block the pores and avoid diffusion of RhB to the liquid phase. Pore opening is produced when specific DNA of HPV is present in the medium, resulting in RhB delivery, that is detected by fluorescence measurements. The sensing assay is optimized for reliable fluorescence signal reading. Nine different sensors are synthesized for specific detection of 14 different hr-HPV types in clinical samples with very high sensitivity (100%) and high selectivity (93-100%), allowing rapid screening of virus infections with very high negative predictive values (100%).
Case 17-2023: A 58-Year-Old Woman with Fatigue, Abdominal Bloating, and Eosinophilia
Authors: Natasha S. Hochberg, Vincent V. Dinculescu, Thomas B. Nutman
Journal: New England Journal of Medicine (2023)

A 58-year-old woman presented with fatigue, abdominal bloating, and eosinophilia. Eight months earlier, she had fractured her tibia while traveling in the Democratic Republic of Congo. A diagnostic test was performed.
Patient-Reported Outcomes after Monitoring, Surgery, or Radiotherapy for Prostate Cancer
Authors: Brian Mcgarry, Ashvin Gandhi, Michael Barnett, T Harvard
Journal: New England Journal of Medicine (2023)

nity prevalence is low, which leads to high rates of false positive results.According to data from the Centers for Disease Control and Prevention and Public Health Ontario, 1,2 during the period included in the study by Stall et al., rates in the United States were 4 times as high as those in Ontario 3 ; in the summer of 2020, U.S. case rates were almost 20 times as high as those in Ontario.Furthermore, even with a low yield, detecting even a single case could produce substantial benefits by preventing a large outbreak.4 The costs and benefits of surveillance testing should be considered in the context of the very low rates of false positive results of surveillance testing that have been found by others.5
2D Ultrathin Iron Doped Bismuth Oxychloride Nanosheets with Rich Oxygen Vacancies for Enhanced Sonodynamic Therapy
Authors: Miaomiao Wu, Jiaxi Yong, Huayue Zhang, Zhiliang Wang, Zhi Ping Xu, Run Zhang
Journal: Advanced Healthcare Materials (2023)

Sonodynamic therapy (SDT) combines ultrasound and sonosensitizers to produce toxic reactive oxygen species (ROS) for cancer cell killing. Due to the high penetration depth of ultrasound (US), SDT breaks the depth penetration barrier of conventional photodynamic therapy for the treatment of deeply seated tumors. A key point to enhance the therapeutic efficiency of SDT is the development of novel sonosensitizers with promoted ability for ROS production. Herein, ultrathin Fe-doped bismuth oxychloride nanosheets with rich oxygen vacancies and bovine serum albumin coating on surface are designed as piezoelectric sonosensitizers (BOC-Fe NSs) for enhanced SDT. The oxygen vacancies of BOC-Fe NSs provide electron trapping sites to promote the separation of e
Eosinophils protect from metabolic alterations triggered by obesity
Authors: Marina Chaves de Oliveira, Ana Letícia Malheiros Silveira, Amanda Carla Clemente de Oliveira, Jaqueline Pereira Lana, Kátia Anunciação Costa, Érica Leandro Marciano Vieira, Vanessa Pinho, Mauro Martins Teixeira, Fatiha Merabtene, Geneviève Marcelin, Karine Clément, Adaliene Versiani Matos Ferreira
Journal: Metabolism (2023)
Intestinal Amino Acid Transport and Metabolic Health
Authors: Stefan Bröer
Journal: Annual Review of Nutrition (2023)

Amino acids derived from protein digestion are important nutrients for the growth and maintenance of organisms. Approximately half of the 20 proteinogenic amino acids can be synthesized by mammalian organisms, while the other half are essential and must be acquired from the nutrition. Absorption of amino acids is mediated by a set of amino acid transporters together with transport of di- and tripeptides. They provide amino acids for systemic needs and for enterocyte metabolism. Absorption is largely complete at the end of the small intestine. The large intestine mediates the uptake of amino acids derived from bacterial metabolism and endogenous sources. Lack of amino acid transporters and peptide transporter delays the absorption of amino acids and changes sensing and usage of amino acids by the intestine. This can affect metabolic health through amino acid restriction, sensing of amino acids, and production of antimicrobial peptides.
Tumor-associated fibrosis impairs immune surveillance and response to immune checkpoint blockade in non–small cell lung cancer
Authors: Brett H. Herzog, John M. Baer, Nicholas Borcherding, Natalie L. Kingston, Jad I. Belle, Brett L. Knolhoff, Graham D. Hogg, Faiz Ahmad, Liang-I Kang, Jessica Petrone, Chieh-Yu Lin, Ramaswamy Govindan, David G. DeNardo
Journal: Science Translational Medicine (2023)

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the Col13a1 -expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor–β receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.
Preventing skin toxicities induced by EGFR inhibitors by topically blocking drug-receptor interactions
Authors: Nethanel Friedman, Liza Weinstein-Fudim, Yelena Mostinski, Jhonatan Elia, Sherri Cohen, Eliana Steinberg, Shoshana Frankenburg, Tamar Peretz, Galit Eisenberg, Michal Lotem, Ofra Benny, Sharon Merims
Journal: Science Translational Medicine (2023)

Epidermal growth factor receptor (EGFR) inhibitors are used to treat many advanced-stage epithelial cancers but induce severe skin toxicities in most treated patients. These side effects lead to a deterioration in the quality of life of the patients and compromise the anticancer treatment. Current treatment strategies for these skin toxicities focus on symptom reduction rather than preventing the initial trigger that causes the toxicity. In this study, we developed a compound and method for treating “on-target” skin toxicity by blocking the drug at the site of toxicity without reducing the systemic dose reaching the tumor. We first screened for small molecules that effectively blocked the binding of anti-EGFR monoclonal antibodies to EGFR and identified a potential candidate, SDT-011. In silico docking predicted that SDT-011 interacted with the same residues on EGFR found to be important for the binding of EGFR inhibitors cetuximab and panitumumab. Binding of SDT-011 to EGFR reduced the binding affinity of cetuximab to EGFR and could reactivate EGFR signaling in keratinocyte cell lines, ex vivo cetuximab-treated whole human skin, and A431-injected mice. Specific small molecules were topically applied and were delivered via a slow-release system derived from biodegradable nanoparticles that penetrate the hair follicles and sebaceous glands, within which EGFR is highly expressed. Our approach has the potential to reduce skin toxicity caused by EGFR inhibitors.
Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration
Authors: Yu Mikami, Barbara R. Grubb, Troy D. Rogers, Hong Dang, Takanori Asakura, Pradeep Kota, Rodney C. Gilmore, Kenichi Okuda, Lisa C. Morton, Ling Sun, Gang Chen, Jason A. Wykoff, Camille Ehre, Juan Vilar, Catharina van Heusden, Alessandra Livraghi-Butrico, Martina Gentzsch, Brian Button, M. Jackson Stutts, Scott H. Randell, Wanda K. O’Neal, Richard C. Boucher
Journal: Science Translational Medicine (2023)

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal airway obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to airway disease, including cystic fibrosis (CF). Consistent with requirements for luminal O 2 , airway epithelia surrounding mucus plugs in chronic obstructive pulmonary disease (COPD) lungs are hypoxic. Despite these observations, the effects of chronic hypoxia (CH) on airway epithelial host defense functions relevant to pulmonary disease have not been investigated. Molecular characterization of resected human lungs from individuals with a spectrum of muco-obstructive lung diseases (MOLDs) or COVID-19 identified molecular features of chronic hypoxia, including increased EGLN3 expression, in epithelia lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic airway epithelia revealed conversion to a glycolytic metabolic state with maintenance of cellular architecture. Chronically hypoxic airway epithelia unexpectedly exhibited increased MUC5B mucin production and increased transepithelial Na + and fluid absorption mediated by HIF1α/HIF2α-dependent up-regulation of β and γENaC (epithelial Na + channel) subunit expression. The combination of increased Na + absorption and MUC5B production generated hyperconcentrated mucus predicted to perpetuate obstruction. Single-cell and bulk RNA sequencing analyses of chronically hypoxic cultured airway epithelia revealed transcriptional changes involved in airway wall remodeling, destruction, and angiogenesis. These results were confirmed by RNA–in situ hybridization studies of lungs from individuals with MOLD. Our data suggest that chronic airway epithelial hypoxia may be central to the pathogenesis of persistent mucus accumulation in MOLDs and associated airway wall damage.
Neutrophil extracellular trap production and CCL4L2 expression influence corticosteroid response in asthma
Authors: Ching-Hui Tsai, Alan Chuan-Ying Lai, Yu-Cheng Lin, Po-Yu Chi, Yun-Chi Chen, Yao-Hsu Yang, Chien-Han Chen, Sheng-Yeh Shen, Tsong-Long Hwang, Ming-Wei Su, I-Ling Hsu, Yu-Chi Huang, Anke H. Maitland-van der Zee, Michael J. McGeachie, Kelan G. Tantisira, Ya-Jen Chang, Yungling L. Lee
Journal: Science Translational Medicine (2023)

The association between neutrophil extracellular traps (NETs) and response to inhaled corticosteroids (ICS) in asthma is unclear. To better understand this relationship, we analyzed the blood transcriptomes from children with controlled and uncontrolled asthma in the Taiwanese Consortium of Childhood Asthma Study using weighted gene coexpression network analysis and pathway enrichment methods. We identified 298 uncontrolled asthma-specific differentially expressed genes and one gene module associated with neutrophil-mediated immunity, highlighting a potential role for neutrophils in uncontrolled asthma. We also found that NET abundance was associated with nonresponse to ICS in patients. In a neutrophilic airway inflammation murine model, steroid treatment could not suppress neutrophilic inflammation and airway hyperreactivity. However, NET disruption with deoxyribonuclease I (DNase I) efficiently inhibited airway hyperreactivity and inflammation. Using neutrophil-specific transcriptomic profiles, we found that CCL4L2 was associated with ICS nonresponse in asthma, which was validated in human and murine lung tissue. CCL4L2 expression was also negatively correlated with pulmonary function change after ICS treatment. In summary, steroids fail to suppress neutrophilic airway inflammation, highlighting the potential need to use alternative therapies such as leukotriene receptor antagonists or DNase I that target the neutrophil-associated phenotype. Furthermore, these results highlight CCL4L2 as a potential therapeutic target for individuals with asthma refractory to ICS.
Impact of prior dengue virus infection on Zika virus infection during pregnancy in marmosets
Authors: In-Jeong Kim, Michael P. Tighe, Madeline J. Clark, Gregory D. Gromowski, Paula A. Lanthier, Kelsey L. Travis, Derek T. Bernacki, Tres S. Cookenham, Kathleen G. Lanzer, Frank M. Szaba, Manasi A. Tamhankar, Corrina N. Ross, Suzette D. Tardif, Donna Layne-Colon, Edward J. Dick, Olga Gonzalez, Maria I. Giraldo Giraldo, Jean L. Patterson, Marcia A. Blackman
Journal: Science Translational Medicine (2023)

Zika virus (ZIKV) infection during pregnancy causes severe developmental defects in newborns, termed congenital Zika syndrome (CZS). Factors contributing to a surge in ZIKV-associated CZS are poorly understood. One possibility is that ZIKV may exploit the antibody-dependent enhancement of infection mechanism, mediated by cross-reactive antibodies from prior dengue virus (DENV) infection, which may exacerbate ZIKV infection during pregnancy. In this study, we investigated the impact of prior DENV infection or no DENV infection on ZIKV pathogenesis during pregnancy in a total of four female common marmosets with five or six fetuses per group. The results showed that negative-sense viral RNA copies increased in the placental and fetal tissues of DENV-immune dams but not in DENV-naïve dams. In addition, viral proteins were prevalent in endothelial cells, macrophages, and neonatal Fc receptor–expressing cells in the placental trabeculae and in neuronal cells in the brains of fetuses from DENV-immune dams. DENV-immune marmosets maintained high titers of cross-reactive ZIKV-binding antibodies that were poorly neutralizing, raising the possibility that these antibodies might be involved in the exacerbation of ZIKV infection. These findings need to be verified in a larger study, and the mechanism involved in the exacerbation of ZIKV infection in DENV-immune marmosets needs further investigation. However, the results suggest a potential negative impact of preexisting DENV immunity on subsequent ZIKV infection during pregnancy in vivo.
Antibody-Associated Reversal of ATTR Amyloidosis–Related Cardiomyopathy
Authors: Marianna Fontana, Janet Gilbertson, Guglielmo Verona, Mattia Riefolo, Ivana Slamova, Ornella Leone, Dorota Rowczenio, Nicola Botcher, Adam Ioannou, Rishi K Patel, Yousuf Razvi, Ana Martinez-Naharro, Carol J Whelan, Lucia Venneri, Amanda Duhlin, Diana Canetti, Stephan Ellmerich, James C Moon, Peter Kellman, Raya Al-Shawi, Laura McCoy, J Paul Simons, Philip N Hawkins, Julian D Gillmore
Journal: New England Journal of Medicine (2023)
The Origins of Covid-19 — Why It Matters (and Why It Doesn’t)
Authors: Lawrence O. Gostin, Gigi K. Gronvall
Journal: New England Journal of Medicine (2023)

hen health emergencies arise, scientists seek to discover the cause -such as how a pathogen emerged and spread -because this knowledge can enhance our under- The Origins of Covid-19 -Why It Matters (and Why It Doesn't)
African governments must build on covid-19 responses to advance gender equality
Authors: Kéfilath Bello, Asha George, Michelle De Jong, Oluwapelumi Adeyera, Cheikh Faye, Taiwo Oyelade, Kedest Mathews, Agnes Binagwaho
Journal: BMJ (2023)

<b>Kéfilath Bello and colleagues</b> argue that building on promising practices to develop more sustainable strategies to advance gender equality will help African countries respond to future crises
Using an intersectionality approach to transform health services for overlooked healthcare users and workers after covid-19
Authors: Mamothena Mothupi, Jashodhara Dasgupta, Seyede Sedighe Hosseini Jebeli, Jacqui Stevenson, Karla Berdichevsky, Sreytouch Vong, Edwine Barasa, Asha George
Journal: BMJ (2023)

Gender equality and PandeMic
Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States
Authors: Anil K. Chaturvedi, Eric A. Engels, Ruth M. Pfeiffer, Brenda Y. Hernandez, Weihong Xiao, Esther Kim, Bo Jiang, Marc T. Goodman, Maria Sibug-Saber, Wendy Cozen, Lihua Liu, Charles F. Lynch, Nicolas Wentzensen, Richard C. Jordan, Sean Altekruse, William F. Anderson, Philip S. Rosenberg, Maura L. Gillison
Journal: Journal of Clinical Oncology (2023)

PURPOSE Recent increases in incidence and survival of oropharyngeal cancers in the United States have been attributed to human papillomavirus (HPV) infection, but empirical evidence is lacking. PATIENTS AND METHODS HPV status was determined for all 271 oropharyngeal cancers (1984-2004) collected by the three population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program by using polymerase chain reaction and genotyping (Inno-LiPA), HPV16 viral load, and HPV16 mRNA expression. Trends in HPV prevalence across four calendar periods were estimated by using logistic regression. Observed HPV prevalence was reweighted to all oropharyngeal cancers within the cancer registries to account for nonrandom selection and to calculate incidence trends. Survival of HPV-positive and HPV-negative patients was compared by using Kaplan-Meier and multivariable Cox regression analyses. RESULTS HPV prevalence in oropharyngeal cancers significantly increased over calendar time regardless of HPV detection assay ( P trend &lt; .05). For example, HPV prevalence by Inno-LiPA increased from 16.3% during 1984 to 1989 to 71.7% during 2000 to 2004. Median survival was significantly longer for HPV-positive than for HPV-negative patients (131 v 20 months; log-rank P &lt; .001; adjusted hazard ratio, 0.31; 95% CI, 0.21 to 0.46). Survival significantly increased across calendar periods for HPV-positive ( P = .003) but not for HPV-negative patients ( P = .18). Population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208% to 242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000), and incidence for HPV-negative cancers declined by 50% (95% CI, 47% to 53%; from 2.0 per 100,000 to 1.0 per 100,000). If recent incidence trends continue, the annual number of HPV-positive oropharyngeal cancers is expected to surpass the annual number of cervical cancers by the year 2020. CONCLUSION Increases in the population-level incidence and survival of oropharyngeal cancers in the United States since 1984 are caused by HPV infection.
The impact of cause of mismatch repair deficiency and other molecular markers on clinical outcomes with the use of durvalumab in advanced endometrial cancer in the phase 2 PHAEDRA trial (ANZGOG1601).
Authors: Daniel D. Buchanan, Khalid Mahmood, Peter Georgeson, Romy Walker, Kristy Robledo, Michelle M. Cummins, Amanda B. Spurdle, Deborah S Smith, Eric Joo, Mark Clendenning, Julia Como, Susan Preston, Sonia Yip, John Andrews, Peey Sei Kok, Yeh Chen Lee, Martin R. Stockler, Linda R. Mileshkin, Yoland Catherine Antill
Journal: Journal of Clinical Oncology (2023)

5604 Background: In the single arm phase 2 PHAEDRA trial, MMR deficiency (dMMR) was predictive of response to durvalumab (1500mg IV Q4W), with an objective tumor response rate (OTR; defined by iRECIST) of 47% in dMMR compared with 3% in MMR-proficient (pMMR) advanced endometrial cancer (AEC). This substudy of the PHAEDRA trial investigates MMR molecular subtypes and other genomic tumor features and their correlation with treatment outcomes. Methods: Testing was performed to determine molecular subtypes of dMMR, including germline pathogenic variants in DNA MMR genes (Lynch syndrome), somatic biallelic MMR gene inactivation through somatic mutation and somatic hypermethylation of the MLH1 gene promoter. DNA from formalin-fixed paraffin-embedded tumor tissue and matched peripheral blood was available from 41/71 (25 dMMR, 16 pMMR) participants for testing on a custom capture-based 298-gene targeted panel (2.005Mb) including the MMR genes and key somatic AEC driver genes. The derived tumor genomic features included microsatellite instability (MSI), tumor mutational burden (TMB), COSMIC v.3.2 tumor mutational signatures and insertion/deletion (Indel) somatic mutation count. Results: Of the 71 patients recruited, 35 were dMMR and 36 were pMMR. Median follow-up was 44 vs 52 months in dMMR vs pMMR participants, respectively. The dMMR molecular subtypes were 4 (11.4%) Lynch syndrome, 4 (11.4%) somatic MMR mutation, 25 (71.4%) MLH1 methylated and 2 (5.7%) dMMR-uncategorised. The OTR rate was 100% (4/4; 95%CI 40-100%) for Lynch, 75% (3/4; 95%CI 22-99%) for somatic MMR mutations and 40% (10/25; 95%CI 22-61%) for MLH1 methylated groups. The median TMB (assessed in 41/71) was higher in those with a confirmed radiological response (37, IQR:26-50) vs non-responders (16, IQR:9-25; p &lt; 0.001). Within the MLH1 methylated group, TMB was also higher in responders vs non-responders (40 v 21; p = 0.03). Somatic mutations in KRAS, PTEN, PIK3CA, ARID1A and TP53 were not associated with OTR rate. Conclusions: dMMR- MLH1 methylated AEC demonstrated greater heterogeneity in OTR to single agent durvalumab than the dMMR-Lynch and dMMR-somatic MMR mutation molecular subtypes. Higher TMB was seen in responders, and specifically within dMMR- MLH1 methylated responders, compared to non-responders. Clinical trial information: ANZGOG1601.